Past early childhood, injury to the central nervous system (CNS) results in functional impairments that are largely irreversible. Within the brain or spinal cord, damage resulting from stroke, trauma, or other causes can result in life-long losses in cognitive, sensory and motor functions, and even maintenance of vital functions. Nerve cells that are lost are not replaced, and those that are spared are generally unable to re-grow severed connections, although a limited amount of local synaptic reorganization can occur close to the site of injury. Functions that are lost are currently untreatable.
Regenerative failure in the CNS has been attributed to a number of factors, which include the presence of inhibitory molecules on the surface of glial cells that suppress axonal growth; absence of appropriate substrate molecules such as laminin to foster growth and an absence of the appropriate trophic factors needed to activate programs of gene expression required for cell survival and differentiation.
By contrast, within the peripheral nervous system (PNS), injured nerve fibers can re-grow over long distances, with eventual excellent recovery of function. Within the past 15 years, neuroscientists have come to realize that this is not a consequence of intrinsic differences between the nerve cells of the peripheral and central nervous system; remarkably, neurons of the CNS will extend their axons over great distances if given the opportunity to grow through a grafted segment of PNS (e.g., sciatic nerve). Therefore, neurons of the CNS retain a capacity to grow if given the right signals from the extracellular environment. Factors which contribute to the differing growth potentials of the CNS and PNS include certain growth-inhibiting molecules on the surface of the oligodendrocytes that surround nerve fibers in the CNS, but which are less abundant in the comparable cell population of the PNS (Schwann cells); molecules of the basal lamina and other surfaces that foster growth in the PNS but which are absent in the CNS (e.g., laminin); and trophic factors, soluble polypeptides which activate programs of gene expression that underlie cell survival and differentiation. Although such trophic factors are regarded as essential for maintaining the viability and differentiation of nerve cells, the particular ones that are responsible for inducing axonal regeneration in the CNS remain uncertain.
Moreover, the intracellular molecule(s) that mediates axonal outgrowth of normal neuronal cells (e.g., upon stimulation with extracellular factors or upstream secondary messangers) has not been elucidated. One report has described the partial isolation of a kinase, referred to as “protein kinase N”, from rat pheochromocytoma PC12 cells that is activated by NGF treatment of the PC12 cells and sensitive to purine regulation (C. Volonte, et al., (1989) J. Cell Biol. 109, 2395–403). However, as PC12 cells are a rat phaeochromocytoma cell line from the adrenal medulla, with many different properties than normal CNS neurons, these cells present a limited model for the processes by which growth of normal CNS neurons is stimulated and the results obtained in PC12 cells may not be predictive of molecules involved in normal CNS neuron growth. Furthermore, this protein kinase N was only partially purified and remains to be molecularly characterized.
In view of the lack of understanding of the molecules involved in mediating axonal outgrowth, effective treatments for CNS injuries have not been developed. Accordingly, elucidation and molecular characterization of such molecules is still necessary, and methods and compositions for modulating the outgrowth of normal CNS neurons by modulating the activity of such molecules are still needed.